STEREOCHEMISTRY OF THE DIELS-ALDER REACTION JAMES G. MARTIN Department of Chemistry, Davihon College, Davidson, North Carolina AND
RICHARD K. HILL Department of Chemistry, Princeton University, Princeton, Neu Jersey
Received January 87, 1961 CONTENTS
I. Introduction..
. . . . .. . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .................................
A. Scope of the review 1. Epimerization of adducts.
.............................. 111. Cisoid conformational requirement of the diene. . . . , . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . A. Evidence from cyclic dienes. . . . . . . . . , , . . . . . . . . . . . . . . B. Effect of substituents on conformation of acyclic dienes.. . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Effect of ring size in homoannular dienes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . IV. The “cis” principle. . . . . . . ..... ..
A. Retention of configurati ienop ............................... B. Retention of configuration of diene substituents . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . V. Stereochemical orientation of the addends. . . . . . . .. . . . .. . .................. A. Endo addition.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Cyclic dienes: endo vs. exo orientation. . . .... 2. Orientation in addition to acyclic dienes.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Quasitheoretical calculations. , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . , . . . . . . . . . . . 4. Competing effects in dienes and dienophiles B. Steric approach control.. . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Steric control of approach to dienophiles.. , . . . . ...... (a) Bis adducts of quinones. . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (b) Norbornene and related dienophiles . . , 2. Steric control of approach to dienes.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . 3. Asymmetric induction in the Diels-Alder re VI. Conclusions.. . . . . . . . . . . . . . . . . . . . . . , . . . . ....................................... VII. References.. .. . . . . . . . . . . . . . . . . . . , ...................................... t
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... .
I
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537 538 538 538 538 538 539 539 540 540 540 542 542 543 544 545 545 545 547 548 549 553 553 553 553 555 556 557 557
I. INTRODUCTION
P
The reaction between a conjugated diene and an o l e h (the dienophile), also usually conjugated, to form a substituted cyclohexene was correctly formulated by Otto Diels and Kurt Alder in 1928 (139) and intensively investigated by them. I n the intervening years it has become one of the most fundamental and useful reactions in the armamentarium of the synthetic organic chemist; in recognition of this importance, its discoverers were awarded the Nobel Prize in Chemistry in 1950. The widespread utility of the reaction rests not only on its ability to form ubiquitous six-membered ring compounds and molecules otherwise difficultly accessible (such as bridged bicyclic compounds), but also on its remarkable stereospecificity. I n the addition of a 1,4disubstituted diene to a 1,Zdisubstituted olefin,
RCH=CH-CH=CHR’
f R”CH=CHR”’
-,
QR“
R//f
R’
for example, no less than eight racemic products could conceivably be formed; the number is doubled by considering, in addition, the alternate structural orientation. Yet the usual result of the reaction is the obtention of one, or a t the most two, stereoisomers. Empirical rules which govern the selection of isomers were formulated by Alder and Stein (45). I n recent years, the selectivity of diene addition has been exploited in stereospecific syntheses of a number of natural products, e.g., cholestanol (308), cortisone (260), reserpine (303), estrone (118), yohimbine (282), cantharidin (276), and conduritol-D (129). 537
538
JAMES G. MARTIN AND RICHARD K. HILL
A. SCOPE OF T H E R E V I E W
The purpose of this review is to focus attention on steric aspects of the Diels-Alder reaction. Purely synthetic and analytic uses of the reaction will not be discussed, nor will the arguments and evidence for the mechanism per se. (The reader may find leading references t o and recent work on the mechanism in references 96, 290, and 306.) The Diels-Alder reaction was last reviewed in this journal in 1942 (238), and other excellent reviews have appeared (3, 5, 112, 168, 186). Applications of the diene synthesis to the chemistry of natural products have been discussed (38). The most thorough previous review of the stereochemistry was the classic article by Alder and Stein in 1937 (45), while certain steric aspects of acyclic diene addition were briefly summarized by Alder in 1951 (4). For the present article the literature has been covered through late 1960, with emphasis on work since 1937.
adduct. Wicks, Daly, and Lack have shown that the double bond of the sorbic acid-maleic anhydride adduct migrates at 160°C. to another position (294), and there is evidence for a similar double-bond shift in the addition of 3,4-dimethyl- 1,3-but adiene to benzoylacrylic acid (170), in the addition of 1,3-butadiene to l-cyano-1,3-butadiene (268), and in additions of 1vinylcyclohexene (231). Migration of the double bond has been suggested as the explanation for the formation of two adducts from 1,l’-bicyclohexenyl and transcinnamic acid (93), but there is no evidence to negate the reasonable assumption that these are instead the two possible normal trans adducts, I and 11.
8Il
I: R = CsHs, R’ = COOH 11: R’ COOH, R‘ = Ce&
B. FACTORS AFFECTING STEREOCHEMICAL CONCLUSIONS
Several pitfalls await the unwary investigator who attempts to draw conclusions about the stereochemical preferences of the Diels-Alder reaction which are based on the observed stereochemistry of isolated products. 1. Epimerization of adducts
Cases have been reported in which the initial adduct was epimerized to a more stable stereoisomer by sufficiently severe reaction conditions. While maleic anhydride and its derivatives ordinarily add to 1,3-butadiene to give derivatives of cis-4-cyclohexene-l,2dicarboxylic acid, in refluxing xylene mono- and diesters of maleic acid give trans adducts (192). 1Phenyl-l,3-butadiene reacts with acrylyl chloride at room temperature to form only cis-2-phenyl-3-cyclohexenecarboxylic acid, but at reflux temperature the product is a mixture of stereoisomers, mostly the trans (207). 3-Ethoxy-l,&pentadiene adds to ethyl 1-methyl-2,5-diketo-3-cyclohexenecarboxylateso slowly that the initial cis ring junction in the product has time to epimerize to the more stable trans (199). Isomerization of the diene may occur before addition; Alder has reported that several cis 1-substituted dienes, on being heated to high temperatures with maleic anhydride, give adducts of the trans diene (35, 36). Epimerization may also occur during workup of the products: the l-phenyl-l,3-butadiene-acroleinadduct isomerizes from cis to trans during purification with sodium bisulfite (54), and alkaline hydrolysis of the cis adduct of cyclopentadiene and dimethyl maleate gives the trans diacid (103). 2. Migration of the double bond
A possible cause for the obtention of isomeric adducts is migration of the cycIohexene double bond of the
3. Reversibility of the Diel*Alder
reaction Diels-Alder adducts dissociate into their components on heating. One consequence of this reversibility is that if two stereoisomeric products are possible, the use of high temperatures and extended reaction times in carrying out additions may permit repeated dissociation and recombination, with the resultant formation of the thermodynamically more stable adduct at the expense of the kinetically favored stereoisomer. An example of this phenomenon was provided by Woodward and Baer (304), who found that at room temperature maleic anhydride added to 6,6-pentamethylenefulvene to form the endo adduct, but at higher temperatures or with longer reaction times, the product was the exo isomer. Similar results have been reported
n
v
co
(2
room c--temperature
oc-0
Endo
-
n
heat
Exo
co
for the addition of other fulvenes t o maleic anhydride (10, 52, 128) and for the addition of furan to maleimide (194). Berson, Remanick, and Mueller (96) have reported recently that heating the optically active endo-methyl methyl methacrylate-cyclopentadiene adduct (111) a t 170°C. for 3 hr. resulted in 7 per cent racemization and 5.6 per cent isomerization to the
STEREOCHEMISTRY OF THE DIELS-ALDER
optically inactive exo-methyl adduct (IV), a result compatible with a dissociation-recombination mechanism.
TABLE 1 Effect of temperature on stereochemistry of the product
111: R = COOCH3, R’ = CHs IV: R = CHs, R‘ = COOCHe
On the other hand, there appears to be an internal process whereby Diels-Alder adducts can undergo thermal rearrangement to stereoisomers without complete separation of the two components. Craig first suggested this possibility for the thermal endo-exo rearrangement of the cyclopentadiene-maleic anhydride adduct (127), and later for the 1,l-dimethylfulvene-maleic anhydride adduct (128). Berson, Reynolds, and Jones (97) demonstrated through the use of a radioactively labeled endo adduct of cyclopentadiene and maleic anhydride that an internal process offered the more facile route for rearrangement, and that isotopic integrity was lost by the slower dissociationrecombination mechanism only after a longer time lapse than was required for initial endo-exo rearrangement. It has been argued that the furan-maleic acid endo-exo rearrangement may also take place through some internal process (98). The remarkable and completely stereospecific thermal rearrangement of the formal Diels-Alder adduct (V) to a structural isomer (VI), which has an important bearing on the mechanism of Diels-Alder addition, mas reported recently by Woodward and Katx (306). Alt>hough the results clearly rule out a solvent-caged mechanism for this rearrangement, such a description is still an attractive alternative for the endo-exo rearrangements described above. h
v
VI
Whatever the mechanism, the effect of temperature on the ratio of stereoisomeric adducts formed is very real and often pronounced; unfortunately, few workers have investigated the temperature factor thoroughly in carrying out Diels-Alder additions. A relevant example of the effect of temperature on the stereochemistry of the product, in the addition of cyclopentadiene to crotonic acid, is shown in table 1, taken from the work of Alder, Giinzl, and Wolff (15). Similar changes in product ratios with temperature have been not,ed in the addition of cyclopentadiene to cinnamic acid (15) and
539
REACTION
COOH A Temperature 0
I
C.
- 10 80 110 170
I
CH3
B ~~
Yield of A
Yield of B
per cent
per cent
85
70
15 30
60 40
40 60
-
methacrolein (209), and of l-phenyl-1,3-butadiene to acrylic acid (54); other cases are cited in Section V,A.
4. D i . u l t y
of separation and analysis of the product The formation of stereoisomeric products offers the usual experimental problem of separation of substances of closely related properties, and there is no doubt that product ratios determined solely on the basis of isolated yields are often inaccurate and occasionally conflicting (15, 217). The development of gas chromatography has made possible the determination of many isomer ratios with a high degree of accuracy (123, 197), as has infrared analysis (106, 128, 131). In a t least one instance, quantitative nuclear magnetic resonance analysis has been employed (183). Errors may arise in the determination of adduct configuration. For example, the standard method of demonstrating the endo configuration of the adduct of a cyclic diene with an unsaturated acid is the interaction of the carboxyl group with the double bond, brought about by such reagents as strong acids or halogens, to form a lactone, sterically impossible in the exo adduct. Yet the reagent may cause skeletal rearrangement of these bridged adducts, and certain exo acids have been demonstrated to yield lactones by rearrangement when treated with sulfuric acid (46, 85, 86) or bromine (25, 286, 305). The milder procedure of iodolactonixation (281) has been shown to be more reliable (253, 286), and the recently introduced method of anilinolactonixation (15) should prove useful. For bicyclic adducts containing hydroxyl groups, the related chloromercuration and iodoetheration procedures have been employed (162, 178).
11. STERIC EFFECTOF SUBSTITUEKTS ON RATES AKD ADDEND-ADDUCT EQUILIBRIA The first step in the addition of a diene to a dienophile is generally regarded as the formation of a loose
540
JAMES G. MARTIN AND RICHARD K. HILL
complex in which the addends lie one above the other in parallel planes (258). While steric effects are thus minimized, it is reasonable to expect that substituents which project much out of the plane of either addend might inhibit complex formation. A related factor is that bulky substituents in the diene or dienophile may be more compressed in the adduct than in the addend, and consequently shift the equilibrium in favor of the components. Such steric effects in the diene seem to be of minor importance. Dienes with bulky substituents, such as l,3-di-tert-butyl-l13-butadiene(79, 146), hexachlorocyclopentadiene (237, 242, 245, 273), and ergosterol (298) still form adducts fairly readily. 9,lO-Dimethylanthracene and 9,lO-diethylanthracene add maleic anhydride much faster than does anthracene (65, 220), and 9,10-diethyl-1,2-benzanthracenereacts more rapidly with maleic anhydride than does benzanthracene itself (74). In the dienophile, however, substituents have a pronounced effect. Simple olefins containing two alkyl groups or halogen atoms on the same carbon atom do not add to hexachlorocyclopentadiene (205). Methyl l-methyl-2,5-diketo-3-cyclohexenecarboxylate (VII), in spite of its resemblance to pbenzoquinone, is a fairly unreactive dienophile (199). Molecules of the type RR’C=CHCOCH=CHz, which provide a built-in competition between substituted and unsubstituted dienophiles, add dienes only on the unsubstituted double bond (230). Pentamethyl- and hexamethylcyclopentadienes do not dimerize readily (287). Cyclohexenones are disappointingly poor dienophiles (84, 171, 252) ; a possible reason is the presence of two hydrogen atoms at C-4 projecting out of the plane (see formula VIII), which interfere with complex formation.
VI I
VI11
A long floppy chain in the dienophile is a powerful inhibitor of the Diels-Alder reaction, undoubtedly for the reasons mentioned a t the beginning of this section. Perry (240) has found that, using standard conditions for the addition of simple dienes to a series of a,&unsaturated acids, RCH=CHCOOH, the reaction fails if R is n-propyl or larger, and in the addition to RCH=CHCOCH3, when R is larger than n-propyl. Stereochemical preferences which appear to be due largely to steric effects are noted in Section V,B. Steric hindrance may affect structural orientation, too ; dienes and dienophiles both substituted with bulky groups give increasingly higher proportions of adducts with the substituents separated as far as possible (232).
111. CISOIDCOXFORMATIONAL REQUIREMENT OF THE DIENE A. EVIDENCE FROM CYCLIC DIENES
Since a trans double bond in a six-membered ring is geometrically impossible, Diels-Alder addition can occur only when the diene possesses a cisoid conformation. A number of transoid cyclic dienes have been shown to be inert, to dienophiles; examples are 3-methylenecyclohexene (228) and P-phellandrene (157) with (X), the diene system (IX), A6~s(14)-cholestadiene A7~9-cholestadiene(XI), and A8~14-cholestadiene(XII) (143), all of which are unreactive to maleic anhydride. The use of addition of maleic anhydride to determine
IX
X
XI
XI1
whether a cyclic conjugated diene is cisoid or transoid has been exploited in structural studies on cholestadienes (95) and abietic acid (81, 295) among others (186). B. EFFECT O F SUBSTITUENTS ON CONFORMATION O F ACYCLIC DIENES
Acyclic dienes are, of course, free to take the cisoid or
e
Cisoid
,”
Transoid
transoid conformation, but Diels-Alder reactions can take place only in the cisoid, or quasicyclic (4),orientation. Steric factors in the diene play a crucial role in determining the relative stability of these two forms, and repulsions which increase the strain energy of the cisoid conformation, relative to the transoid, have an adverse effect on diene addition. One such factor is a cis 1-substituent on the diene; the nonbonded interaction between the substituent R and the cis 4-hydrogen makes the cisoid conformation more difficult to achieve. Accordingly, it is uniformly true that a trans 1-substituted 1,3-butadiene reacts with dienophilea
m I (H R Cisoid
w I I H R Transoid
much more readily than the cis isomer. Since the cis isomer usually polymerizes faster than the trans (151), many attempts to add dienophiles to cis 1-substituted dienes have led only to copolymers. Goldman has shown recently (156) that polymerization may often be avoided by carrying out the reaction under nitrogen, with 5-10 per cent by weight of added hydroquinone.
STEREOCHEMISTRY O F THE DIELS-ALDER
Even so, the difference in reactivity is so pronounced that addition of maleic anhydride can be used as a method of quantitatively separating the cis and trans isomers. trans-Piperylene forms adducts with acrylonitrile (151) and maleic anhydride (125), using conditions under which the cis isomer does not react. Craig has shown (126) that cis-piperylene can be induced to add maleic anhydride and fumaric acid, but only under much more drastic conditions than are required for the trans isomer. traras-l-Phenyl-l,3-butadienegives a quantitative yield of the maleic anhydride adduct on refluxing in toluene for 4 hr., while the cis compound reacts to the extent of only 5 per cent (158). cis-1,3,5Hexatriene adds maleic anhydride readily, while the trans isomer does not react (173). trans-1-Ethyl-1,3butadiene forms a maleic anhydride adduct easily in boiling benzene, though the cis isomer is inert (7, 57); the same is true of the trans and cis isomers of l-cyano1,3-butadiene (270). Similar differences in reactivity have been observed for several pairs of trans,trans and cis,trans 1,4-disubstituted dienes: 1,4-dimethyl-1,3(130), butadiene (57), 1,2,3,4-tetramethyl-1,3-butadiene 4-methyl-l-phenyl-l,3-butadiene(37), 1,4-diphenyl-1,3butadiene (35), and Pcarbomethoxy-l-phenyl-l,3-butadiene (36). Alder and von Brachel have shown that several trans,trans,ciEi trienes, e.g., XIII, which contain both cis and trans 1-substituted diene systems to which addition could take place, add maleic anhydride only to the trans,trans end (7).
REdCTION
54 1
conformations, as in the ergosterol series (298), add dienophiles readily. Cis substituents a t both ends of an acyclic 1,Pdiene further decrease the reactivity, to the point where the Diels-Alder reaction does not occur. Hexachloro-1,3butadiene does not give adducts with maleic anhydride or benzoquinone (152), and cis,cis-1,4-diphenyl-1,3butadiene is completely unreactive toward dienophiles (35). When conditions under which trans,trans-1,4diacetoxy-1,3-butadiene adds quantitatively to juglone are employed, the cis,trans isomer reacts in only 47 per cent yield and the cis,cis isomer not a t all (176). The 1,1,4,4-tetramethyl- and tetraethyl-l,3-butadienes do not add to a-naphthoquinone (150). Two further indications of the extreme unreactivity of the tetramethyl compound are (a) it reacts with maleic anhydride only at very high temperatures, after first rearranging to 4-isopropyl-2-methyl-l,3-butadiene (229), and (b) it reacts with the “benzyne” intermediate by substitutive addition rather than 1,Paddition (67). \
I
The difference in reactivity between cis and trans 1-substituted dienes with maleic anhydride has been utilized in the determination of the stereochemistry of a number of natural dienes and polyenes (38, 213). By this method dimorphecolic acid (XIV) was shown to be a trans,trans diene (266), the dehydration product (XV) of ricinelaidic acid (“Mangold’s acid”) was also shown to be a trans,trans diene (24), and the configuration of the diene substituent in the pyrethrolones (XVI) was shown to be trans (132). Configurations have also 1,l-Disubstituted 1,3-butadienes, which must have a been assigned to the triene systems in a- and P-eleocis 1-substituent, add dienophiles with reluctance, and several early investigators were doubtful that additsion stearic acids (XVII) (24, 100) and their isomer punicic acid (144), a- and 6-licanic acids (XVIII) (216), the occurred at all (72, 73, 80, 163, 198, 277). Under forcing isomers of the tetraene, parinaric acid (XIX) (184), conditions, however, adducts have been formed from allo- and neoalloocimene (XX) (13, 117), and a series l,l-dimethyl-l,3-butadiene (133, 1,1,2-trimethyl-l,3butadiene (156, 219), 1,1,3-trimethyl-1,3-butadiene of simple trienes (7) by the use of the Diels-Alder reaction. This method was also of great utility in elu(140, 179, 180, 200, 201), 1-methyl-2-vinylcyclohexene cidating the structure and stereochemistry of irradiation (156),and 1,3-dimethyl-2-vinylcyclopenteneand cyclohexene (156). In the series 1,1,4,4-tetraphenyl-1,3- products of ergosterol (149). butadiene to 1,1,12,12-tetraphenyldodecahexaene,the CHa( CH*)aCHaCHCH=CHCHOH( CHo)iCOOH terminal cis phenyl substituents inhibit the cisoid XIV conformation of the terminal pairs of conjugated double CHs(CHt)sCH=CHCH=CH( CH2)rCOOH bonds, preventing their addition to dienophiles; XV the interior diene systems are not affected by the substituents and react readily (34). Several texts (153, 165) HO CH*CH=CHCH=CHt have proposed that the difficulty in adding dienophiles to 1,l-disubstituted dienes is due to the direct steric XVI repulsion of the dienophile by the substituents, but this factor appears to have only secondary significance, CHa(CH2)a(CH=CH)r(CHi)GOOH XVII since other dienes similarly substituted but in k e d cisoid
‘
Eo
542
JAMES G . MARTIN AND RICHARD K. H I L L
CHs( CHz)a(CH=CH)a( CHz)rCOCH&H&OOH XVIII CHsCHz(CH=CH)d( CHz)&OOH
XIX ( CHs)zC.=CHCH=CHC( CH:)=CHCH:
xx Bulky substituents a t the 2- and 3-positions of a f,4-diene also influence the conformational equilibrium in the diene and consequently the ease of Diels-Alder addition. It is seen that when R and R' are large,
Cisoid
Transoid
(115), and Cava and Mitchell have trapped benzocyclobutadiene as its adduct with N-phenylmaleimide (114). 1,3-Cycloheptadiene is less reactive than the fiveand six-membered dienes, but still forms adducts easily (18, 25, 189). With dienes having rings of medium size, however, the reaction suddenly fails. l,&Dienes in rings of eight to eleven members do not form adducts with maleic anhydride (102, 124, 147, 313). The reason for this seems clear: models reveal that a planar cisoid conformation of the diene in these rings is too highly strained to be stable, a conclusion reinforced by the low intensity of their ultraviolet absorption (102, 147). Two geometrical isomers of 1,3-~yclodecadieneare known, the cis,cis and cis,traiis, but neither has a planar cisoid diene system and neither reacts with maleic anhydride (102). Cyclooctatetraene, which also lacks a planar diene system, reacts with maleic anhydride only after isomerization to bicyclo [4.2.0]octa-2,4,7-triene which adds the dienophile to the cyclohexadiene moiety (243). Rings larger than eleven atoms again permit the cisoid diene conformation, and 1,a-dienes in 12-, 13-, 14-, and 18-membered rings add maleic anhydride, albeit in low yield (83, 174). The adducts of the latter three were dehydrogenated to interesting para-bridged phthalic anhydrides (XXIII) (174, 296).
~tericrepulsions are considerably lower in the transoid conformation than in the cisoid, and Diels-Alder reactions are accordingly difficult. 2,3-Di-tert-butyl-l13butadiene is the best example; it is completely inert to dienophiles (78), although the 1,3-isomer adds maleic anhydride (79, 146). 2,3-Dichloro-1,3-butadieneis reported not to react with maleic anhydride or naphthoquinone (89). 2,3-Dimethyl-1,3-butadiene,on the other hand, is a notorious partner in Diels-Alder though reactions (238), and 2,3-diphenyl-1,3-butadiene, sluggish, reacts with several dienophiles (62, 63), which may indicate that the phenyl groups can twist out of coplanarity. Both 1,2,3,4-tetraphenyl-1,3-butadiene and 1,2,4-triphenyl-1,3-butadieneadd maleic anhydride under vigorous conditions (19). XXIII Also falling in the category of bulkily 2,3-disubstituted dienes are 9-(a-styry1)phenanthrene (XXI) and IV. THECIS PRINCIPLE 9,9'-biphenanthryl (XXII), which do not react with The cardinal stereochemical principle of the Dielsmaleic anhydride, in contrast to simpler vinylphenanAlder reaction was recognized early and formulated threnes (90, 92). as the first of the classical Alderatein rules: the "cis" principle (45). Aside from the factors listed in Section I,B, which are independent of the reaction itself and its mechanism, no exceptions are known to the rule that the relative configuration of the starting materials is retained in the adduct; the reliability of the rule is one of the major factors in the importance of the Diels-Alder reaction in synthesis and in stereochemical XXI XXII studies.1 An explanation for this behavior, in modern terms, is that after t8hediene and dienophile have been 0. E F F E C T OF R I N G SIZE I N HOMOANNULAR DIENES joined by one bond, the partial formation of the new A final factor which influences diene conformation is bond and the secondary attractive forces in the transithe ring size of homocyclic dienes. Cyclopentadiene tion state serve to prevent any rotation which might end 1,3-cyclohexadiene, both containing fixed cisoid lead to inversion of the relative configurations a t the conformations, readily take part in Diels-Alder reactermini of the addends (306). tions, especially the former (238). It has been postulated 1 It is noteworthy that even when catalyzed by a molar equivakhat the dimers which result from attempts to prepare lent of aluminum chloride, Diels-Alder addition of anthracene derivatives of cyclobutadiene are formed by Dielsto maleic anhydride and dimethyl fumarate retains its stereospecificity (309). AJder additions of the extremely reactive intermediates
STEREOCHEMISTRY OF T H E DIELS-ALDER
TABLE 2 (Continued)
-4. R E T E N T I O N O F COXFIGURATION O F D I E N O P H I L E SURSTITUEXTS
Table 2 gives a partial listing of Diels-Alder reactions for which there is sound experimental evidence that the relative configuration of the dienophile substituents is unchanged in the adduct. It is now tacitly assumed that all Diels-Alder reactions obey this rule, but only those cases for which some independent evidence of the stereochemistry of the adduct is available are included in the table.
Dienophile
Diene and Reference ~~
Cyclopentene-l-carboxaldehyde. . . . 2-Methyl-2-cyclohex-lenone. Cyclohexen-2-one. . 3-Methyl-3-cyclopentene1,a-dione , ,
. . ....... ............... . .. . .. . . . . ... . . . .
3,B-Dihydrophthalic acid, Bicyclo [2.2.1 lheptene. . . . p-Benzoquinone . . , , , , , , ,
TABLE 2 Retention of configuration of dienophile substituents Diene and Reference
Dienouhile Acyclic: Maleonitrile. , Dimethyl maleate. Fumario acid..
. . .. . . . . . . .... . . . . .. . . . . . Dihydromuconitrile.. . . . .
Dimethyl fumarate..
.. . .
.. . . . .
Fumaronitrile. . . . . . . Mesaconic acid and derivatives. . . . . . . . . . .
..
Diethyl glutaconate. . . Crotonic acid and isocrotonic acid. . . . . . . . . . Crotonaldehyde . . . . . . . . . cis- and trans-Cinnamic . . . acids.
..
. ... . . . . . . . . .
.... . Benzoylacrylic acid.. . . . . l-Nitropropene . . . . . . . . . . ,%Nitrostyrene. . . . . . . . . . Benzalacetone . . . . .
CoHaSOzCH=CHCOOH. fl-Haloaorylio acids. . 1,2-Diacetylethylene.
. ... .. . .
Cyclic: Maleic anhydride.. . . . . . .
..
. . .. ..
Maleimide. . . . . . . . N-Phenylmaleimide.. . . Phenylmaleic anhydride. Dimethylmaleic anhydrid, Citraconic anhydride.
.
. ..
. . ... .. .. . .
Cyolopentadiene . Vinylene carbonate..
Cyclohexene-l-carboxaldehyde. . . . . . .
.
. . . ..
4-Methoxytoluquinone.,
ao
@;:m;.. . . . . . . . .
Anthracene (76), cyclopentadiene (9,224), 1,3-cycloheradiene (Q), l-vinylnaphthalene (77), l-vinylcyclohexene (222) 1,3-Butadiene (164, 240) Cyclopentadiene (15) 1,3-Butadiene (140) 1,3-Butadiene (54), cyclopentadiene (15), 2-ethoxy-1,3-butsdiene (171), 1,1'-bicyclohexenyl (93) 1 , l'-Bicyclohexenyl (93), Z-ethoxy-l,3-butadiene (171) Cyclopentadiene (217), 2,3-dimethyl-1,3butadiene (170) Anthracene (236), cyclopentadiene (283) Anthracene (236), 1,3-butadiene (69), cyclopentadiene (292) Cyclopentadiene (215) Cyclopentadiene (16) l,a-Butadiene, 2,3-dimethyl-1,3-butadiene, cyclopentadiene, 1,3-~yolohexadiene(262) Anthracene (76), 1,3-butadiene (45), furan (305), cyclopentadiene (61), 1,3-cyclohexadiene (53), 1,3-cycloheptadiene (25), 1vinylnaphthalene (771, l-alkyl-l,3-butadienes (7, 126), hexa-, hepta-, and octatrienes (7), 1,4-dialkyl-l,3-butadienes (7, 13, 57), 1,4-diphenyl-1.3-butadiene (35), 4-methyl-l-phenyl-l,3-butadiene (37), methyl 4-phenyl-1,3-butadiene-lcarboxylate (36), alloocimene (13), eleostearic acids (24), 1,2,4-triethylnaphthalene (188), l-vinylcyclohexene (193), 1,2dimethyl-1,3-butadiene (193) Furan (194) 1,2-Dimethylene-3,5-cyolohexadiene (113) Cyclopentadiene (9, 218) 1,3-Butadiene (307) Cyclopentadiene (9, 224). 1,3-cyclohexadiene (9), anthracene (76), l-vinylnaphthalene (77), 3,4-dihydro-6-methoxy2-vinylnaphthalene (75, 161), I-acetoxy1,3-butadiene (193) Cyclopentadiene (47) Cyclopentadiene (61), 1,4-diacetoxy-l,3butadiene (129) 1.3-Butadiene (91)
Qo
.
.............. .
Cyclopentadiene (103) Indene (27), anthracene (76) 1,a-Butadiene (1911, anthracene (76), l-vinylnaphthalene (77) Cyolopentadiene (26) l-Acetoxy-1,3-butadiene (193), anthracene (76) Cyclopentadiene (103)
543
REACTION
.
. . . . . . , . ... *
1,a-Butadiene (91) 1,3-Butadiene (154) l-Vinylcyclohexene (233) 1,a-Butadiene (265), 3,4-dihydro-8-methoxy-l-vinylnaphthalene (265) 1,a-Butadiene (6) 1,3-Butadiene (26) 1,a-Butadiene (42), cyclopentadiene (42), 1,3 - cyclohexadiene(42), 1 - vinylcyclohexene (249), vinylacrylic acid (303), 3,4dihydro - 6 - methoxy-l-vinylnaphthalene (251), 3-ethoxy-1,3-pentadiene (99, 261) 1,3-Butadiene (308), piperylene (104) 1,3-Butadiene (196) 1,a-Butadiene (276) l,3-Butadiene diene (171)
(172),
2-ethoxy-1,3-buta-
1,3-Butadiene (172)
In addition to the reactions cited in table 2, there are a number of cases in which stereoisomeric dienophiles lead to stereoisomeric adducts, but for which retention of configuration, while almost certain, has not been specifically proved. Among these are the addition of cis- and trans-dibenzoylethylenes to cyclopentadiene (l), the addition of maleic and fumaric acid derivatives (64)and to 2,5-dimethyl-3,4-diphenylcyclopentadienone di(1-cyclohexeny1)acetylene ( l l l ) , the addition of cis- and trans-o-methoxycinnamic acids to 2,3-dimethyll,&butadiene (a),and the addition of hexachlorocyclopentadiene to cis- and trans-cyclooctenes and ciqcisand trans1trans-1,5-cyc100ctadienes (31 1). The butadiene-dimethyl maleic anhydride adduct (XXIV) was hydrogenated to desoxycantharidin (307), and the adduct (XXV) of l13-butadienewith dimethyl 3,6-epoxy-3,4,5,6-tetrahydrophthalatewas the intermediate used by Stork, van Tamelen, Friedman, and Burgstahler in an ingenious synthesis of cantharidin itself (276). The use of vinylene carbonate as a COOCH3
COOCH, XXIV
xxv
dienophile provides a new route to cis-l12-glycols (61, 235) and sugar derivatives (129). Numerous attempts have been made to synthesize members of the steroid family by Diels-Alder reactions Earlier work, using 3,4-dihydro-l-vinylnaphthalenes
544
JAMES G. MARTIN AND RICHARD K. HILL
as the diene and five-membered dienophiles such as 3methyl-3-cyclopentene- l12-dione (75, 136, 265), was plagued by the obtention of both the wrong structural isomer and the wrong (C/D cis) stereoisomer:
OCHB
The adduct (XXVI) of p-benzoquinone with the above diene (R = OCH3), however, has been successfully transformed into estrone (118). Recent applications of
served as a similar origin of the D and E rings of yohimbine (282). B. RETENTION O F CONFIGURATION O F D I E N E SUBSTITUENTS
0
XXVI
the Diels-Alder reaction have made available nonaromatic steroids in unnatural configurations (221, 234). More modest uses of the Diels-Alder reaction in steroid synthesis, in constructing only two rings of the skeleton, have met with outstanding success. Both the Harvard synthesis (308) and the Monsanto synthesis (82, 274) utilize the adduct of 1,3-butadiene and methoxytoluquinonejn building rings C and D:
R
In contrast to the large number of substituted dienophiles which give adducts of known stereochemistry, relatively few cases have been investigated which provide unambiguous evidence for the configurational fate of diene substituents. Every reported example, however, substantiates the rule of cis addition and resulting retention of relative configuration of substituents on the 1- and 4-positions of the diene. These are listed in table 3. Cyclic l,&dienes in rings of medium TABLE 3 Retention of configuration of diene substituents A. Trans,trans 1,4disubstituted dienes
(+
